The rate and assessment of muscle wasting during critical illness: a systematic review and meta-analysis

Background Patients with critical illness can lose more than 15% of muscle mass in one week, and this can have long-term detrimental effects. However, there is currently no synthesis of the data of intensive care unit (ICU) muscle wasting studies, so the true mean rate of muscle loss across all studies is unknown. The aim of this project was therefore to systematically synthetise data on the rate of muscle loss and to identify the methods used to measure muscle size and to synthetise data on the prevalence of ICU-acquired weakness in critically ill patients. Methods We conducted a systematic literature search of MEDLINE, PubMed, AMED, BNI, CINAHL, and EMCARE until January 2022 (International Prospective Register of Systematic Reviews [PROSPERO] registration: CRD420222989540. We included studies with at least 20 adult critically ill patients where the investigators measured a muscle mass-related variable at two time points during the ICU stay. We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and assessed the study quality using the Newcastle–Ottawa Scale. Results Fifty-two studies that included 3251 patients fulfilled the selection criteria. These studies investigated the rate of muscle wasting in 1773 (55%) patients and assessed ICU-acquired muscle weakness in 1478 (45%) patients. The methods used to assess muscle mass were ultrasound in 85% (n = 28/33) of the studies and computed tomography in the rest 15% (n = 5/33). During the first week of critical illness, patients lost every day −1.75% (95% CI −2.05, −1.45) of their rectus femoris thickness or −2.10% (95% CI −3.17, −1.02) of rectus femoris cross-sectional area. The overall prevalence of ICU-acquired weakness was 48% (95% CI 39%, 56%). Conclusion On average, critically ill patients lose nearly 2% of skeletal muscle per day during the first week of ICU admission. Supplementary Information The online version contains supplementary material available at 10.1186/s13054-022-04253-0.


Introduction
Critical illness is defined as the deterioration of an illness resulting in a deranged homeostasis. This leads to life-threatening organ dysfunction requiring advanced organ support techniques, and therefore it is associated with high morbidity and mortality. Both the underlying disease and the causes for the unfavourable course of the disease are diverse and often end in further secondary organ dysfunctions, which are referred to as multi-organ failure. Organ dysfunction, sepsis, prolonged mechanical ventilation, and immobility are risk factors for muscle wasting which leads to ICU-acquired weakness (ICU-AW) [1].
ICU-AW is an umbrella term that describes a bundle of neuromuscular disorders that develop due to admission in the intensive care unit and severe illness [2]. The pathophysiology of ICU-AW is incompletely understood; however, ICU-AW appears to be triggered by critical illness and its severity during the ICU is independent of the underlying primary condition [3][4][5]. The hallmarks of the ICU-AW are an inflammatory response, bioenergetic dysfunction, altered protein balance, neuronal axon degeneration, changes in muscle histology, and muscle wasting [6,7]. During critical illness, factors such as immobilisation and altered neuroendocrine responses cause muscle wasting by making protein balance negative [8]. On the other hand, muscle dysfunction is caused by multiple factors including microcirculatory disturbances reducing oxygen supply, bioenergetic mitochondria impairment causing reduced ATP production, and disruptions in the ion channels membrane [9]. These conditions in addition to the patients immobilisation and malnutrition make muscle wasting the dominant phenotype of acquired muscle weakness in critically ill [10].
Patients with critical illness lose muscle mass and muscle function with limited treatment options. Specifically, muscle wasting starts early in the first week of critical illness and patients with multi-organ failure lose more muscle mass than other patients [11]. Observational studies have reported that muscle wasting is associated with a longer stay on ICU [12,13], and higher ICU [14] and hospital mortality [15]. They also noted that muscle wasting is associated with acquired weakness [16,17]. However, to date there is no study that has summarised published data on the daily amount of muscle that is lost in ICU patients, the methods used to monitor muscle size in those patients, and on the prevalence of ICU-AW in critically ill patients.
To address this issue, we carried out a systematic review and meta-analysis aiming to answer the following research questions: 1. What is the rate of muscle wasting in critically ill patients? 2. What are the methods used to assess changes in muscle mass in critically ill patients? 3. What is the incidence of ICU-AW in critically ill patients? 4. What are the outcomes (i.e. mortality, mechanical ventilation time, and length of stay) associated with muscle wasting?

Methods
The study protocol was registered and published on 13 January 2022 on the International Prospective Register of Systematic Reviews (PROSPERO) of the National Institute for Health Research (NIHR) under the ID CRD42022298954. We conducted this systematic review and meta-analysis in accordance with the Joanna-Briggs Institute (JBI) Reviewer's Manual for Systematic Reviews of Literature [18] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines [19,20].

Definitions
The measurement of the rectus femoris is taken by placing the transducer perpendicular to the long axis of the tight on its superior aspect, three-fifth of the distance from the anterior superior iliac spine to the superior patella border. This is the highest point in the tight that the entire rectus femoris cross section can be visualised in a single field. The cross-sectional area is calculated by a planimetric technique after the inner echogenic line of the rectus femoris is outlined by a movable cursor on a frozen image [21]. The quadriceps femoris muscle include vastus medialis, vastus lateralis, vastus intermedius, and rectus femoris.

Search strategy
We conducted our search on MEDLINE (National library of medicine: Bethesda, MD) and AMED, BNI, CINAHL, and EMCARE. Studies were also identified and retrieved by citation searching from the references of each relevant study, as reported in Fig. 1.
For the initial literature search, we used a combination of MeSH terms and key terms including (muscle mass OR muscle atrophy OR muscle wast* OR muscle loss OR muscle weakness OR muscle strength OR muscle function OR intensive care unit acquired weakness OR ICU-AW) AND (critical* ill* OR critical care OR intensive care unit OR ICU).
We included studies that were published between 1 January 2000 and 31 January 2022.
The references of all included papers, review articles, commentaries, and editorials on this topic were reviewed to identify other relevant studies which were missed during the primary search. If necessary, we contacted the corresponding authors to obtain data necessary for our study. No language restrictions were applied. Three investigators (BF, TM, and CC) independently screened title and abstracts in duplicate for selection of full-text review. If a decision was not achieved from reading the title and abstract alone, the full text was reviewed. The reviewers also independently reviewed the full text of relevant studies and decided on eligibility. Inter-rater disagreements in the study selection were resolved by consensus or if necessary, by consultation with a senior author (HW). A flow chart of the whole process is presented according to PRISMA guidelines 2020 in Fig. 1.

Study inclusion and exclusion criteria
Eligible studies included adult women and men (age > 18 years old) admitted to any critical care facility (ICU/high dependency unit [HDU]) receiving invasive or non-invasive mechanical ventilation. Large treatment effects have been reported in studies including fewer patients [22]; hence, we included all peer-reviewed studies enrolling leastwise 20 critically ill patients who had assessment of muscle mass or ICU-AW at any time point after the day of admission or at two time points during ICU stay. We excluded (i) studies published prior 1 January 2000, (ii) reviews and meta-analysis, (iii) book chapters, comments, editorials, (iv) guidelines and consensus report, (v) protocol studies, and (vi) case studies, case reports.

Data extraction
Three reviewers (BF, TM, and CC) extracted the following information from each publication into an Excel file: date of publication, country, study design, number  of included patients, age, gender, clinical features, laboratory findings, severity and outcome of the disease  (including health-related quality of life, cognitive status,  mental health, physical function, muscle and/or nerve  function, and pulmonary function). Data extraction was performed in duplicate by three authors acting independently (BF, TM, and CC). A flow chart of the whole process is presented according to PRISMA guidelines 2021 in Fig. 1. The characteristics of the studies included are presented in Table 1.

Risk of bias assessment
Three reviewers (BF, TM, and CC) independently assessed the risk of bias using the Newcastle-Ottawa Scale (NOS) for observational studies [14], and the Cochrane Risk of Bias tool (ROB2) was used for assessing randomised controlled trial [23]. Risk of bias across studies was assessed using the approach outlined by the Grading of Recommendations Assessment Development and Evaluation (GRADE) working group [15,16]. Any disagreements were recorded and resolved by involvement of an additional reviewer.

Data synthesis and analysis
A narrative and tabular synthesis of the findings from the included studies was provided. Data were grouped into the main outcomes above specified. Numerical data on the long-term outcomes above specified were collected for quantitative analysis.

Statistical analysis
Mean and standard deviation (SD) or median and interquartile range (1st quartile to 3rd quartile) were used for numerical data if appropriate, while odds ratio (OR) with 95% confidence interval (CI) was used for categorical data. For data presenting median and interquartile range (IQR) or median and range, mean and standard deviation (SD) were transformed according to standard equations [17][18][19]. The studies included for meta-analysis were pooled together using the random-effects model accounting for the incidence. The results were presented in forest plots. Heterogeneity among studies was evaluated using the Tau 2 test, I 2 statistics, and Cochrane Q. A p value < 0.05 was considered as evidence of publication bias. Analysis of data was performed using the statistical software packages Review Manager 5.4 (RevMan 5.4.1 ® ) and OpenMeta [Analyst] ® .

Results
We identified 10,496 studies through our literature search. After removing duplicates and publications that did not fit our inclusion criteria, we were left with 53 publications. Of these, 33 quantify muscle wasting over time with 4 studies measuring muscle wasting and ICU-AW and 20 studies assess ICU-AW only. See Fig. 1 to appreciate the flow diagram of the studies included.
Overall, the publications reported data on 3251 patients, 1773 (55%) on muscle wasting, and 1478 (45%) for ICU-acquired weakness. We found 1 randomised controlled trial and 43 single-centre and 8 multi-centre observational studies across Australia, Asia, USA, South America, and Europe. Studies' characteristics are summarised in Tables 1 and 2.
The observational studies assessed with the Newcastle-Ottawa Scale were found to have relatively low risk of bias being all good quality (6*). The randomised controlled study was assessed with the ROB scale, and we found fair risk of bias specifically about blinding of participants and personnel and blinding of outcome assessment (refer to the Additional File 1).

Assessment methods
We analysed the methods used to assess muscle wasting and found that of the 33 studies that measured muscle size, 28 (85%) studies used ultrasound [11-17, 24-31, 31-44] and 5 studies (15%) used computed tomography (CT) [45][46][47][48][49] at different time points. Additional methods used in conjunction with ultrasound and CT were the ratio of protein to DNA and histopathological analyses [11], bioelectrical impedance analysis [31], and the urea-to-creatinine ratio in blood [48]. This reveals a high degree of inconsistency in assessing muscle mass as different studies analyse different muscles at different time points during critical illness. The main muscles assessed using ultrasound were rectus femoris, quadriceps muscle, and biceps brachii with measurements taken for cross-sectional area or thickness. The areas measured on CT were the skeletal muscle cross-sectional area at the third vertebrae (L3) level and the cross-sectional area of the femoral muscle volume using sagittal direction integration.

Changes in muscle mass
During the first week of critical illness, patients lost on average every day −1.75% (95% CI −2.     PC prospective cohort, RC retrospective cohort, RCT randomised controlled trial, ICU intensive care unit, MRC sum muscle power assessment scale, SAPS simplified acute physiology score underestimate muscle loss compared with cross-sectional area (p < 0.001). This was also similar for bicep brachii [37]. The loss in muscle mass for all the muscles measured over the course of ICU stay is presented in Fig. 2.
The L4 psoas and L3 muscle cross-sectional area both progressively decrease over time (R 2 0.64 and 0.59, respectively), and the skeletal muscle wasting is accompanied by elevated urea/creatinine ratio.
One RCT [46] assessing femoral muscle volume in patients receiving high-protein versus medium-protein intake found that muscle volume loss at day 10 (assessed using CT scan) was significantly lower in patients receiving high-protein (high-protein group: 12.9 ± 8.5% versus medium-protein group: 16.9 ± 7.0%, p = 0.0059). Total energy delivery was around 20 kcal/kg/day in both groups, but protein delivery was 1.5 g/kg/day and 0.8 g/ kg/day. Early active rehabilitation was also provided to both groups. A second RCT [44] comparing the effect of continuous versus intermittent feeding found that muscle loss at day 10 (i.e. rectus femoris muscle cross-sectional area determined by ultrasound) was similar between arms (−1.1% [95% CI, −6.1% to −4.0%]; p = 0.676). Intermittently fed patients received 80% or more of target protein (OR, 1.52 [1.16-1.99]; p < 0.001) and energy (OR, 1.59 [1.21-2.08]; p = 0.001).

Outcomes associated with muscle wasting
A meta-analysis of outcomes associated with muscle wasting was not possible as studies assessed various outcomes differently. For example, the outcome of mortality was not equally assessed and in a study was evaluated 60-day mortality [70], or in-hospital mortality [28], or mortality in ICU [71].
A study noted that patients with multi-organ failure lost muscle mass early and that the loss was more severe when compared to patients with single organ failure [11]. In patients with sepsis and septic shock, the changes of rectus femoris cross-sectional area were reported to be significantly higher (17.5%) in mechanically ventilated patients compared to those without ventilation (10.76%), p = 0.001 [27]. Early decline in biceps brachii mass was found a predictor for mortality [28]. Additionally, a study noted that over the first week of critical illness, every 1% loss of quadriceps femoris muscle thickness was associated with 5% increase in 60-day mortality [adjusted OR 0.95 (95% CI 0.90, 0.99) p = 0.023] [15]. A logistic regression analysis noted that patients who lost more than 10% of quadriceps femoris muscle thickness at day 7 had higher probability to remain on mechanical ventilation   [14]. During the first week in intensive care, more than 10% loss of rectus femoris cross-sectional area was associated with longer ICU length of stay (p = 0.038), hospital length of stay (p = 0.014), and mechanical ventilation time (p = 0.05) [12].
In patients with sepsis and acute respiratory distress syndrome, muscle wasting during the first 7 days of ICU was found to be a predictor for ICU-acquired weakness (area under the curve = 0.912) [16]. Patients presenting with muscle wasting and ICU-acquired weakness on day 3 had longer mechanical ventilation time (p = 0.006) and ECMO (p = 0.025) compared to those with no ICU-AW [13].

Discussion
In this systematic review, we pooled results from 53 studies from international settings including 3251 critically ill patients. Our main findings are that (1) 85% of studies used ultrasound to assess muscle mass with measurements taken at the rectus femoris, quadriceps muscle and biceps brachii cross-sectional area or thickness; (2) during the first week of critical illness, patients lose roughly 2% of muscle mass per day, and muscle mass decreases over the course of the ICU stay; and (3) half of the critically ill patients have ICU-acquired weakness.
There is no consensus on how to quantify muscular changes in critically ill patients. In our analysis, ultrasound was the most frequently used method. This is probably because ultrasound devices are portable and can be used directly at the bedside of the patient. In contrast, CT requires transferring the patient to the scanner, which is risky and may not always be possible depending on the clinical stability of the critically ill patient.
The use of ultrasound is reliable (intraclass correlation coefficient, > 0.75 for all comparisons) when considering interobserver correlation for quantitative analysis of muscle parameters in critically ill patients [72]. Use and interpretation of ultrasound measurements are not without challenges, as there is considerable methodological variability in the measurement technique to quantify muscle mass. Specifically, the cross-sectional area and muscle layer thickness are different measurements and do not account for the same volume. It has been shown that for assessment of rectus femoris measuring the muscle layer thickness significantly underestimated ICU muscle wasting compared with cross-sectional area [40]. Furthermore, ultrasound-based quadriceps muscle layer thickness (QMLT) did not accurately estimate muscle loss when compared to quantifications of computed tomography (CT)-based muscle cross-sectional area (CSA) [73]. A study found that measuring cross-sectional area may be a more reliable proxy for muscle strength and could be used as a biomarker for proximal lowerlimb muscle loss and knee extensor weakness during early critical illness in settings where volitional and nonvolitional muscle strength measurements are challenging [40].
The incidence rate of ICU-AW was high (48%), and our findings may be an under-representation of the actual prevalence, as this depends upon the diagnostic evaluation used. We noted that electrophysiological examination resulted in the detection of more individuals with ICU-AW. This is potentially attributed to the fact that clinical examinations have a certain extent of subjectivity, and the diagnosis is partially determined by the clinician's decision. On the other hand, electrophysiological assessments are standardised with clear cut-off values and instructions for the diagnosis. However, this difference can also result from methodological dissimilarity in assessing ICU-AW, such as the timing of diagnosis, the lack of homogeneity between patient populations and variable assessment frequency.

Strength and limitations
Our systematic review is the first to quantify the overall rate of muscle loss in critically ill, but has limitations. Firstly, there was a high degree of inconsistency in assessing muscle mass since studies assessed different muscles and different measurements methods at different time points during critical illness. Therefore, a differentiation of muscle loss for individual illnesses was not possible and thus remained unanswered. Second, the pre-admission baseline characteristics and patient functional state were limited. Consequently, it was not possible to assess the impact on muscle loss by severity of critical illness or pre-existing comorbidities. Finally, the studies inconsistency in assessing outcomes made a meta-analysis of outcomes associated with muscle wasting not possible. The recent CONCISE Delphi consensus should provide further guidance for authors assessing outcomes related to muscle wasting [74].

Conclusion
Critically ill patients suffer from early and marked muscle wasting. Ultrasound is the most used assessment tool in evaluating loss in muscle mass over time. The muscle mass is about 2% per day, but this rate is different between muscles and depends upon the measurement taken. The prevalence of ICU-AW is 50% amongst critically ill and those have worst outcomes.